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Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors

Author

Listed:
  • Elisa I. Rivas

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Jenniffer Linares

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Melissa Zwick

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Andrea Gómez-Llonin

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Marc Guiu

    (Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST))

  • Anna Labernadie

    (Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute for Science and Technology (BIST))

  • Jordi Badia-Ramentol

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Anna Lladó

    (Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST))

  • Lídia Bardia

    (Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST))

  • Iván Pérez-Núñez

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Carolina Martínez-Ciarpaglini

    (Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia)

  • Noelia Tarazona

    (Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia)

  • Anna Sallent-Aragay

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Marta Garrido

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Toni Celià-Terrassa

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

  • Octavio Burgués

    (Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia)

  • Roger R. Gomis

    (Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST))

  • Joan Albanell

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
    Hospital del Mar
    Universitat Pompeu Fabra
    Centro de Investigación Biomédica en Red de Oncología (CIBERONC-ISCIII))

  • Alexandre Calon

    (Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM))

Abstract

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients’ response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

Suggested Citation

  • Elisa I. Rivas & Jenniffer Linares & Melissa Zwick & Andrea Gómez-Llonin & Marc Guiu & Anna Labernadie & Jordi Badia-Ramentol & Anna Lladó & Lídia Bardia & Iván Pérez-Núñez & Carolina Martínez-Ciarpag, 2022. "Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32782-3
    DOI: 10.1038/s41467-022-32782-3
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    References listed on IDEAS

    as
    1. Nadim Aizarani & Antonio Saviano & Sagar & Laurent Mailly & Sarah Durand & Josip S. Herman & Patrick Pessaux & Thomas F. Baumert & Dominic Grün, 2019. "A human liver cell atlas reveals heterogeneity and epithelial progenitors," Nature, Nature, vol. 572(7768), pages 199-204, August.
    2. Jerod L. Ptacin & Carolina E. Caffaro & Lina Ma & Kristine M. San Jose Gall & Hans R. Aerni & Nicole V. Acuff & Rob W. Herman & Yelena Pavlova & Michael J. Pena & David B. Chen & Lilia K. Koriazova & , 2021. "An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Kosuke Yoshihara & Maria Shahmoradgoli & Emmanuel Martínez & Rahulsimham Vegesna & Hoon Kim & Wandaliz Torres-Garcia & Victor Treviño & Hui Shen & Peter W. Laird & Douglas A. Levine & Scott L. Carter , 2013. "Inferring tumour purity and stromal and immune cell admixture from expression data," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    4. Floriane Pelon & Brigitte Bourachot & Yann Kieffer & Ilaria Magagna & Fanny Mermet-Meillon & Isabelle Bonnet & Ana Costa & Anne-Marie Givel & Youmna Attieh & Jorge Barbazan & Claire Bonneau & Laetitia, 2020. "Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    5. Jan Budczies & Frederick Klauschen & Bruno V Sinn & Balázs Győrffy & Wolfgang D Schmitt & Silvia Darb-Esfahani & Carsten Denkert, 2012. "Cutoff Finder: A Comprehensive and Straightforward Web Application Enabling Rapid Biomarker Cutoff Optimization," PLOS ONE, Public Library of Science, vol. 7(12), pages 1-7, December.
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    Cited by:

    1. Jenniffer Linares & Anna Sallent-Aragay & Jordi Badia-Ramentol & Alba Recort-Bascuas & Ana Méndez & Noemí Manero-Rupérez & Daniele Lo Re & Elisa I. Rivas & Marc Guiu & Melissa Zwick & Mar Iglesias & C, 2023. "Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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